Prior to antiretroviral therapy (ART) including highly active ART (HAART), lung diseases were the major cause of death in AIDS patients. While ART has dramatically improved the morbidity and mortality in HIV-infected subjects, the incidence of chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, and asthma remain high in this population. Smoking is highly prevalent in HIV-infected patients and smoking is the leading cause of COPD and chronic bronchitis in humans; however, with a similar smoking history COPD is more common and appears at younger age in HIV-infected than uninfected smokers. Recent reports suggest HIV as possible independent risk factors for the development of COPD. COPD is a progressive obstructive lung disease with no known cure. A common feature of COPD, asthma, and chronic bronchitis is overproduction of airway mucus. While airway mucus is important in the mucociliary clearance of inhaled pathogens and particulates, excessive mucus contributes to airway obstruction and is an excellent medium for the growth of many pathogens, which may accelerate the disease and cause COPD exacerbations. Our recent results indicate that, in spite of ART, SIV- and HIV-infected lungs contain substantial amounts of mucus and gp120 immunoreactivity. Moreover, cell culture studies indicated that primary cultures of normal human bronchial epithelial (NHBE) cells express CD4 and CXCR4 but not CCR5 and are productively infected by X4HIV-1. Moreover, as little as 10 ng/ml ? 8 x 10-11M X4-HIV gp120, induces mucus production and mucous cell hyperplasia/metaplasia in NHBE cells. Mucus production induced by HIV-1 gp120 is regulated by CXCR4, nicotinic acetylcholine receptors, and ?-aminobutyric acidA receptors. In rodent models, increasing evidence shows a synergy between cigarette smoke and some viral infections in the development of COPD. Based on these studies, we hypothesize that HIV-1 and cigarette smoke synergizes to accelerate the development of COPD, and HIV-gp120 promotes COPD exacerbation through excessive mucus production in the lung. Indeed, recent evidence links SHIV infection to airway obstructive changes in cynomolgus monkeys. In this grant application we propose to use cynomolgus macaques, SHIV infection, and HAART (combination of tenofovir, emtrictabine, and elvitegravir) to ascertain independent and/or synergistic roles of HIV, and cigarette smoke in the development of COPD (aim 1), and delineate the mechanism by which HIV-gp120 promotes mucus formation in NHBE cells (aim 2). We believe that this is the first study to understand the interaction between smoking, HIV infection, and ART in the development of COPD and will provide information that will help to reduce the incidence of COPD in HIV-infected subjects.